Summary Alzheimer's disease is the most common form of dementia, accounting for 70 to 80% of all cases. The pathology of the disease consists primarily of amyloid-beta plaques and neurofibrillary tangles composed of microtubule-associated protein tau (also known as MAPT). In a widely-used mouse model for Alzheimer's, secreted A? monomers produced from processing of the Amyloid Precursor Protein (APP) disrupts cognitive function, yet little to no neuropathology including neurofibrillary tangle formation or neuronal loss is observed. Developing a model that recapitulates both plaques and tangles, the twin hallmarks of the human disease would be beneficial in understanding the pathogenesis of Alzheimer's disease (AD). In up to 50% of late-onset, sporadic cases of Alzheimer's, proteinopathy of the TDP-43 protein has been reported as an age-related copathology. TDP-43 functions as a heterogeneous nuclear ribonucleoprotein (hnRNP), with two RNA recognition motifs, nuclear localization and export signals, and a glycine-rich domain involved in protein-protein interactions. TDP-43 participates in exon skipping, RNA stability, RNA transport, splicing, translation, micro RNA processing, and other cellular functions. Similar to tau, pathological TDP-43 becomes hyper-phosphorylated and is present largely as neuronal inclusions, or less frequently in glial cells. Although accumulation of TDP-43 in AD is considered a secondary pathology, we hypothesize that TDP-43 is functionally involved in APP regulation and tau aggregation. We have developed a mouse model that selectively drives expression of human TDP-43 in the hippocampus and cortex in an APP/PS1 (AD model) mouse background. TDP-43 overexpression reduces amyloid-beta (A?) plaque deposition through lysosomal mislocalization of APP and aggregates phosphorylated Tau, which is not normally seen in these mice and is more similar to what is seen in human AD. We further describe an interaction between TDP-43 and the Ca2+/calmodulin-dependent protein phosphatase, calcineurin in which changes in TDP-43 expression inversely regulate calcineurin expression. Since calcineurin is known to regulate neuronal activity, long-term depression and depotentiation, synaptic plasticity and memory, we hypothesize that changes in TDP-43 expression, through the protein itself and through regulation of calcineurin expression, have profound effects on the changes in memory, network connectivity, and pathology associated with Alzheimer's disease. Our overall experimental approach is to determine if there is a functional relationship between TDP-43 expression and AD-related pathology, and deficits in behavior, and network connectivity by up- and down- regulating TDP-43 expression in an Alzheimer's disease mouse model and evaluating the modulation of plaque deposition and tau aggregation in neurons, changes in memory and anxiety in the animals, and functional changes in network connectivity. Utilizing magnetic resonance imaging (MRI) optimized for rodents in the CBBI core, with AD model mice in which TDP-43 expression can be turned on and off will allow us to assess the functional relationship between TDP-43 expression and synaptic network connectivity. Functional network connectivity will be evaluated through resting state fMRI and manganese-enhanced MRI to visualize changes in pre- and post-synaptic neuronal pathway connectivity related to changes in TDP-43 expression. Imaging the mice as they age, as plaque deposition increases and behavioral deficits become more pronounced in APP/PS1 mice, and comparing them to those with increased and decreased TDP-43 expression will indicate whether modulating TDP-43 expression could provide a target of therapeutic intervention to slow the progression of this devastating disease!